Estudo da eficácia e segurança de compostos heterocíclicos no contexto da infecção pelo Trypanosoma cruzi e na prevenção de danos ao DNA

Abstract

Among the 21st century’s public health paradigms, the search for therapeutic alternatives for orphan diseases represents an urgent need in the world’s scenario. Heterocyclic compounds constitute a class of chemical entities of great importance for the organization of living matter, since more than half of all known chemical compounds are heterocyclic, with emphasis on the drugs, vitamins and active principles in plants and marine organisms. A class widely investigated in the context of Trypanosoma cruzi infection and revealing promising trypanocidal activity is that of arylimidamides (AIAs), oxygenated heterocyclic compounds that associate non-intercalatingly with DNA. Nitroimidazole compounds are nitrogen-containing heterocyclics, which carry the nitro group (NO2) and are highly relevant in medicinal use. Statins are competitive inhibitors of the HMGCoA-reductase enzyme widely used in the treatment of hypercholesterolemias. Atorvastatin is considered the last and largest of the blockbusters (drug more profitable) in the history of synthetic pharmacology. The pleiotropic effects of statins have been studied for more than a decade. Our objective was to investigate the efficacy, safety and selectivity of synthetic heterocyclic compounds with the potential to prevent DNA damage and in the context of parasitic infections such as T. cruzi. We evaluated the in vitro trypanocidal activity of the heterocyclic compounds on amastigotes and trypomastigotes of T. cruzi in monotherapy and in combination with benznidazole schemes, in addition to evaluating the cytoarchitectonic arrangement in cardiomyocytes infected or not with T. cruzi. The prevention of DNA damage was evaluated in bacterial and eukaryotic models. In addition, the mutagenic and toxicity profile on mammalian cells were evaluated by the Ames test, micronucleus assay and cell viability. Our data demonstrated that mono-AIAs are in addition to less effective also less selective than the bis-AIAs on T. cruzi. The results of analysis of the structure-activity relationship of nitroimidazoles demonstrate that the nitro group is not alone responsible for the mutagenic or genotoxic activity, with the substituents closely playing an important role in modulating its toxicity. Atorvastatin was able to prevent DNA damage, reversing dysfunctions in the cell cycle of hepatocytes exposed to genotoxic stress, exerted sequestering activity of DPPH + radicals suggesting that its chemoprotective effect is associated with the sequestration of potentially genotoxic radicals. Atorvastatin presented a good profile of trypanocidal activity when used alone, thus exhibiting synergistic interaction with benznidazole in the combination therapy trials, leading to an increase in the efficacy and selectivity of both. Two of its phenylacetic derivatives showed moderate trypanocidal activity alone against the blood trypomastigotes of the Y strain. The brominated derivative was considered genotoxic and the chlorinated derivative demonstrated a safe profile for the tests recommended by the regulatory toxicology agencies. Atorvastatin exhibited repositioning potential as a trypanocidal and cytoprotective drug, mainly in combination therapies and one of its new derivatives showed a hit-to-lead profile in experimental chemotherapy against T. cruzi. The heterocyclic compounds, represented in this study by the classes of arylimidamides, nitroimidazoles and statins, are indicated as promising alternatives for the treatment of Chagas Disease.